Abstracts

Rationale: Two DBA mouse models of sudden unexpected death in epilepsy (SUDEP) are known. Currently, the only effective pharmacological preventative therapy for sudden death in these SUDEP models is the administration of fluoxetine, which acts as a selective serotonin re-uptake inhibitor (SSRI). Several subtypes of serotonin (5-hydroxytryptamine, 5-HT) receptors exist, and the increase in 5-HT availability induced by SSRIs would likely activate all of these receptor subtypes, potentially leading to elevated adverse effects. Therefore, 5-HT receptor subtype-selective agents that are currently under development have the potential to be effective in activating 5-HT receptors that may be most closely involved in the susceptibility of the DBA mice to SUDEP. Therefore, the present study examined the effect of a 5-HT2B/2C agonist, m-chlorophenylpiperazine (mCPP) on seizure-induced sudden death in DBA/1 and DBA/2 mice.Methods: DBA/1 (N=29) and DBA/2 (N=44) mice (8-15g, 21-35 days old) were evaluated for susceptibility to audiogenic seizure-induced respiratory arrest (RA), using an electrical bell at 122 dB SPL, re: 0.0002 dyne/cm in a cylindrical chamber. Behaviors were recorded on video, and seizure parameters were quantified visually off-line. Mice that exhibited seizure-induced RA were resuscitated using a rodent respirator. At least 24 hr later mice exhibiting seizure-induced RA were given mCPP, (2-60 mg/kg (i.p.) and tested for AGS-induced RA 30 min after drug administration.Results: In DBA/2 mice, seizure-induced-RA was significantly (p <0.05, Wilcoxon signed rank test) reduced 30 min after mCPP administration (10 mg/kg), and the effect on RA was relatively selective, since the mice remained susceptible to audiogenic seizure at the same time. Return to susceptibility to seizure-induced RA was observed 24 hr after drug administration. On the other hand, mCPP in doses up to 60 mg/kg were not effective in blocking seizure-induced RA in DBA/1 mice and the 60 mg/kg mCPP was toxic to these mice.Conclusions: The 5-HT2B/2C agonist, mCPP, was effective in blocking seizure-induced RA in the acutely susceptible SUDEP model in DBA/2 mice, which is consistent with previous results with fluoxetine in these mice. However, the inability of mCPP to block seizure-induced RA in DBA/1 mice is perplexing. Previous data has shown that expression of specific 5-HT receptor subtype proteins were abnormal in DBA/2 mice. Thus, expression of specific 5-HT2C, 5-HT3, and 5-HT4 receptor proteins in the brainstem of DBA/2 mice is significantly diminished, while expression of the 5-HT2B receptors is significantly enhanced as compared to normal C57BL/6J mice (Uteshev et al., 2010). On the other hand, recent preliminary data on the expression of specific 5-HT receptor proteins in the brainstem of DBA/1 mice indicate a pattern of change that differs significantly from that in DBA/2 mice, which may account for the differential effects of the selective 5-HT2B/2C agonist in the two mouse models of SUDEP. Support: Citizens United to Cure Epilepsy